title: Thiazolopyridine ureas as novel antitubercular agents acting through inhibition of DNA Gyrase B.
abstract: A pharmacophore-based search led to the identification of thiazolopyridine ureas as a novel scaffold with antitubercular activity acting through inhibition of DNA Gyrase B (GyrB) ATPase. Evaluation of the binding mode of thiazolopyridines in a Mycobacterium tuberculosis (Mtb) GyrB homology model prompted exploration of the side chains at the thiazolopyridine ring C-5 position to access the ribose/solvent pocket. Potent compounds with GyrB IC50 ≤ 1 nM and Mtb MIC ≤ 0.1 μM were obtained with certain combinations of side chains at the C-5 position and heterocycles at the C-6 position of the thiazolopyridine core. Substitutions at C-5 also enabled optimization of the physicochemical properties. Representative compounds were cocrystallized with Streptococcus pneumoniae (Spn) ParE; these confirmed the binding modes predicted by the homology model. The target link to GyrB was confirmed by genetic mapping of the mutations conferring resistance to thiazolopyridine ureas. The compounds are bactericidal in vitro and efficacious in vivo in an acute murine model of tuberculosis.
authors.affiliation: Department of Medicinal Chemistry, ‡Department of Biosciences, and §DMPK and Animal Sciences, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Manoj G
authors.initials: MG
authors.lastname: Kale
authors.forename: Anandkumar
authors.initials: A
authors.lastname: Raichurkar
authors.forename: Shahul Hameed
authors.initials: SH
authors.lastname: P
authors.forename: David
authors.initials: D
authors.lastname: Waterson
authors.forename: David
authors.initials: D
authors.lastname: McKinney
authors.forename: M R
authors.initials: MR
authors.lastname: Manjunatha
authors.forename: Usha
authors.initials: U
authors.lastname: Kranthi
authors.forename: Krishna
authors.initials: K
authors.lastname: Koushik
authors.forename: Lalit kumar
authors.initials: Lk
authors.lastname: Jena
authors.forename: Vikas
authors.initials: V
authors.lastname: Shinde
authors.forename: Suresh
authors.initials: S
authors.lastname: Rudrapatna
authors.forename: Shubhada
authors.initials: S
authors.lastname: Barde
authors.forename: Vaishali
authors.initials: V
authors.lastname: Humnabadkar
authors.forename: Prashanti
authors.initials: P
authors.lastname: Madhavapeddi
authors.forename: Halesha
authors.initials: H
authors.lastname: Basavarajappa
authors.forename: Anirban
authors.initials: A
authors.lastname: Ghosh
authors.forename: V K
authors.initials: VK
authors.lastname: Ramya
authors.forename: Supreeth
authors.initials: S
authors.lastname: Guptha
authors.forename: Sreevalli
authors.initials: S
authors.lastname: Sharma
authors.forename: Prakash
authors.initials: P
authors.lastname: Vachaspati
authors.forename: K N Mahesh
authors.initials: KN
authors.lastname: Kumar
authors.forename: Jayashree
authors.initials: J
authors.lastname: Giridhar
authors.forename: Jitendar
authors.initials: J
authors.lastname: Reddy
authors.forename: Vijender
authors.initials: V
authors.lastname: Panduga
authors.forename: Samit
authors.initials: S
authors.lastname: Ganguly
authors.forename: Vijaykamal
authors.initials: V
authors.lastname: Ahuja
authors.forename: Sheshagiri
authors.initials: S
authors.lastname: Gaonkar
authors.forename: C N Naveen
authors.initials: CN
authors.lastname: Kumar
authors.forename: Derek
authors.initials: D
authors.lastname: Ogg
authors.forename: Julie A
authors.initials: JA
authors.lastname: Tucker
authors.forename: P Ann
authors.initials: PA
authors.lastname: Boriack-Sjodin
authors.forename: Sunita M
authors.initials: SM
authors.lastname: de Sousa
authors.forename: Vasan K
authors.initials: VK
authors.lastname: Sambandamurthy
authors.forename: Sandeep R
authors.initials: SR
authors.lastname: Ghorpade
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D027081:DNA Gyrase / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D014376:Tuberculosis / Q000188:drug therapy*; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000995:Antitubercular Agents; D011725:Pyridines; D059005:Topoisomerase II Inhibitors; D014508:Urea; D027081:DNA Gyrase